Hantavirus pulmonary distress syndrome (HPS) is a highly lethal disease caused by infection with one of a number of New World hantaviruses. Sin Nombre virus (SNV) has been associated with HPS cases in North America while Andes virus (ANDV) has been implicated in a number of HPS outbreaks in South America. Human infections are thought to result from inhalation of aerosolized rodent urine, but there is strong evidence suggesting human to human transmission with ANDV. The rapid disease progression, high mortality and morbidity, and potential for human to human transmission associated with the agents of HPS make them potential candidates for use as bioterrorism weapons. We intend to apply recent technological advances in viral genome manipulation tools and primary cell culture systems to the study of ANDV and SNV replication and virulence in the hopes of gaining more insight into the factors responsible for HPS. The proposed studies will serve to advance our knowledge of HPS pathogenesis as well as lay the groundwork for the rational design of HPS vaccines and therapies.